1. Field of the Invention
This invention relates to biomedical devices possessing microbiocidal or antimicrobial properties. It also relates to control of sessile bacterial growth, especially that growth at the point of contiguity between device and body tissues.
2. Description of Related Art
U.S. Pat. No. 3,755,224 discloses vinyl chloride compositions possessing biocidal properties and articles thereof wherein the compositions are produced from a vinyl chloride resin containing a 3-isothiazolone and a liquid plasticizer.
U.S. Pat. No. 4,086,297 discloses solid thermoplastic resin compositions containing from 1 to 80% of a microbiocide wherein the microbiocide and a first thermoplastic resin composition are blended and further mixed with a second thermoplastic resin to provide resistance against microbiocidal attack on the second thermoplastic resin composition. Neither of these patents disclose the use of such materials for biomedical devices.
U.S. Pat. No. 4,105,431 discloses the maximum dilution of 3-isothiazolone which will control several organisms. However, the patent does not disclose the treatment of living hosts.
U.S. Pat. No. 3,896,813 discloses natural or synthetic suture material impregnated with an antibiotic to protect the suture material from biological contamination during storage.
Van Noort et al., J. Biomed. Materials Res. 13, 623-630 (1979), discloses silicone rubbers useful for hydrocephalus shunts impregnated with gentamicin sulfate.
Greco et al., Ann. Surg., 195 (No. 2), 168 (1982), discloses polytetrafluoroethylene grafts bonded to oxacillin (a negatively charged antibiotic) using a cationic surfactant-benzalkonium chloride. The bonded grafts are useful to combat local contamination with Staph. aureus when placed in the infrarenal aorta of dogs.
The last three references all use naturally occurring antibiotics which give rise to resistant strains of bacteria.
See also U.S. Pat. No. 4,381,380 and references cited therein. U.S. Pat. No. 4,381,380 describes urethane cathethers made biocidal by soaking in iodine solutions. The drawbacks are that iodine is irritating, particularly, to mucosal surfaces. Iodine cannot be incorporated uniformly into a polymer because of volatility. The use of iodine is limited to urethanes which complex the iodine. Isothiazolones, however, can be used with a wide variety of useful elastomers, particularly rubber, silicone and plasticized vinyl.
"Antibiotic" means a chemical substance produced by microorganisms which has the capacity, in dilute solutions, to inhibit the growth of or to destroy bacteria and other microorganisms and is intended to embrace both naturally-produced (by microorganisms) and synthetic chemicals. Although antibiotics control a wide variety of living pathogenic organisms which occur in living mammalian hosts, many hosts demonstrate allergic responses when treated with antibiotics. Microorganisms tend to develop resistant mutants or strains upon exposure to naturally derived antibiotics. Further, antiobiotics are difficult and costly to produce on a large scale. Also, heat causes antibiotics to lose their activity.
I have observed that the increasing use of a variety of medical prostheses made of a variety of materials including, for example, natural and synthetic rubbers, silicone rubbers, silicone plastics, polyvinyl chloride (PVC), tetrafluoroethylene polymer, polyethylene, polypropylene, stainless steel, tantalum, nylons, and dacron, have been associated with infections in adjacent body tissues. This phenomenon has been observed especially with indwelling devices; such as, skeletal joint replacements, cardiac valves, indwelling catheters, vascular prostheses, vascular access devices for hemodialysis, cardiac shunts, pacemakers, intrauterine devices, intraperitoneal devices, and organ implants.
The bacteria that cause these infections often grow on the surfaces of these prostheses and are resistant to conventional antibiotic therapy. The bacteria that adhere to the surfaces of the indwelling devices are the same bacteria which, when occurring in the body, can be controlled by conventional antibiotic therapy. However, when these bacteria adhere to the surfaces of an indwelling device they associate in colonies. These colonies are highly resistant to control by conventional antibiotic therapy. The colonies constitute a continual source of bacteria which cause re-infections when conventional antibiotic therapy is withdrawn.
The freely occurring bacteria are planktonic bacteria. The bacteria which cause the recurring infections are sessile bacteria.
Conventional antibiotics are usually effective in controlling the planktonic bacteria in the body, but are not effective in controlling the sessile bacteria.
"indwelling devices" are those biomedical devices which may be implanted in the body of the host so that the biomedical device is in contact with adjacent body tissues.
"Microorganisms" includes living pathogenic bacteria and fungi (including molds and yeasts).
For these reasons, biomedical devices are needed which control the microorganisms which form sessile colonies in living hosts.
This invention provides a biomedical device for controlling bacteria which comprises:
(a) an elastomer having a Tg below 25.degree. C., selected from natural rubber, synthetic rubber, silicone rubber, polypropylene, polyamide or polyurethane, having incorporated therein or coated thereon, PA1 (b) an effective amount of an isothiazolone of the formula: ##STR1## wherein Y is hydrogen, unsubstituted or substituted C.sub.4 -C.sub.18 alkyl, unsubstituted or substituted C.sub.2 -C.sub.18 alkenyl or alkynyl, an unsubstituted or substituted C.sub.3 -C.sub.12 cycloalkyl, unsubstituted or substituted C.sub.6 -C.sub.10 aralkyl, or unsubstituted or substituted C.sub.6 -C.sub.10 aryl; R is hydrogen, halo, or C.sub.1 -C.sub.4 alkyl; R.sup.1 is hydrogen, halo, or C.sub.1 -C.sub.4 alkyl.
If the isothiazolone is unstable, it is stabilized with at least one metal salt in an amount of about 1 to 60 weight percent, based on weight of isothiazolone and metal salt, said metal salt being represented by the formula: (MX.sub.n) wherein M is a cation of a metal selected from sodium, potassium, calcium, magnesium, copper, iron, zinc, barium, manganese, silver, cobalt, or nickel; X is an anion selected from chloride, bromide, iodide, sulfate, nitrate, nitrite, acetate, chlorate, perchlorate, bisulfate, bicarbonate, oxalate, maleate, p-toluenesulfonate, carbonate, or phosphate; and n is an integer for which the anion X satisfies the valence of the cation M.
Preferred isothiazolones are those wherein Y is unsubstituted or substituted C.sub.6 -C.sub.18 alkyl, unsubstituted or substituted C.sub.4 -C.sub.18 alkenyl or alkynyl, an unsubstituted or substituted C.sub.5 -C.sub.12 cycloalkyl, unsubstituted or substituted C.sub.6 -C.sub.10 aralkyl, or unsubstituted or substituted C.sub.6 -C.sub.10 aryl; R, R.sup.1, M, X and n are as defined above. These compounds have a lower water solubility and, therefore, would release slower from the devices than the more water soluble materials.
The most preferred compounds are those isothiazolones wherein Y is C.sub.6 -C.sub.12 alkyl, benzyl, phenethyl, halobenzyl, halophenethyl, at least one of R and R.sup.1 is chloro or bromo. These compounds have a water solubility of less than 1000 ppm.
This invention also comprises a method for inhibiting the growth of sessile bacteria on a device in a living host which comprises contacting said bacteria with a therapeutically effective amount of microbiocidal material in the biomedical device.
It should be noted that, as the number of carbon atoms in the substituent group "Y" increases, and as halogens are substituted on the isothiazolone ring, water solubility decreases.
"Therapeutically effective amount" is an amount generally in the range of from about 0.03 to about 5 percent by weight and, preferably, in the range of from about 0.05 to 1 percent by weight.
It should be understood that this invention also embraces non-elastomeric materials coated with the products of this invention in a film forming matrix to form devices which perform as well as those prepared solely from elastomers.
"Substituted alkyl" is an alkyl having one or more of its hydrogens replaced by another substituent. Examples include hydroxyalkyl, haloalkyl, cyanoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, carboxyalkyl, carbalkoxyalkyl, alkoxyalkyl, aryloxyalkyl, alkylthioalkyl, arylthioalkyl, haloalkoxyalkyl, cycloaminoalkyl such as morpholinylalkyl and piperidinylalkyl and pyrrolodinylalkyl and the like, carbamoxyalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, isothiazolonylalkyl, and the like.
"Substituted aralkyl" is an aralkyl having one or more of its hydrogens (either on the aryl or the alkyl) replaced by another substituent. Examples of substituted aralkyls include halo-, lower alkyl-, or lower alkoxy-substituted aralkyl groups.
"Substituted aryl" is an aryl such as phenyl, naphthyl, or pyridyl, having one or more of the hydrogens on the aryl ring replaced by another substituent. Examples of such substituents include halo, nitro, lower alkyl, lower alkoxy, lower alkylamino, acylamino, lower carbalkoxy, sulfonyl, and the like.
The term "isothiazolone(s)" include both the non-complexed 3-isothiazolone(s) and the metal salt complexes of the 3-isothiazolone(s).
Representative "Y" substituents include butyl, hexyl, octyl, decyl, pentadecyl, octadecyl, cyclopentyl, cyclohexyl, benzyl, 3,4-dichloro-benzyl, 4-methoxybenzyl, 4-chlorobenzyl, 3,4-dichlorophenyl, diethylaminoethyl, cyanoethyl, carbomethoxyethyl, 2-methoxy-1-bromoethyl, 3,3,5-trimethylcyclohexyl, phenoxyethyl, 2-chloroanilinomethyl, phenylcarbamoxymethyl, hexenyl, decynyl, carboxyethyl, 1-isothiazolonylethyl, 1,2,2,-trichlorovinyl, phenethyl and p-chlorophenethyl.
Representative "R" substituents include hydrogen, bromo, chloro, iodo, methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl.
Representative "R.sup.1 " substitutents include hydrogen, chloro, bromo, iodo, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, chloromethyl, bromomethyl, bromoethyl, and bromopropyl.
Typical compounds within the scope of formula I include: 2-tert-octyl-3-isothiazolone, 2-decyl-3-isothiazolone 2-octyldecyl-3-isothiazolone, 2-cyclohexyl-3-isothiazolone, 4-chloro-2-hexyl-3-isothiazolone, 4-bromo-2-octyl-3-isothiazolone, 5-chloro-2-decyl-3-isothiazolone, 5-chloro-4-cyclohexyl-3-isothiazolone, 4-bromo-5-chloro-2-methyl-3-isothiazolone, 4-bromo-2-cyclohexyl-3-isothiazolone, 4,5-dichloro-2-hexyl-3-isothiazolone, 4-methyl-2-octyl-3-isothiazolone, 4,5-dimethyl-2-octyl-3-isothiazolone, 2-benzyl-3-isothiazolone, 2-benzyl-4,5-dichloro-3-isothiazolone, 2-benzyl-5-chloro-3-isothiazolone, 2-(2',4'-dichlorobenzyl)-3-isothiazolone, 2-(4'-ethylbenzyl)-3-isothiazolone, 2-(3',4'-dichlorophenyl)-3-isothiazolone, 2-(3',3',5'-trimethyl-cyclohexyl)-3-isothiazolone, 2-(2-phenoxyethyl)-3-isothiazolone, 2-phenylcarbamoxymethyl-3-isothiazolone, 2-(3'-chloro-phenylcarbamoxymethyl)-3-isothiazolone, 2-(3',4'-dichlorophenylcarbamoxymethyl)-3-isothiazolone, 2-[2-(4'-chlorophenyl)ethyl]-3-isothiazolone, 2-n-hexyl-3-isothiazolone, 2-n-heptyl-3-isothiazolone, 2-cyclopentyl-3-isothiazolone, 2-(4'-chlorophenyl)-3-isothiazolone, 2-(2',4'-dichlorophenyl)3-isothiazolone, 2-(2',3'-dichlorophenyl)-3-isothiazolone, 2-(2',5'-dichlorophenyl)-3-isothiazolone, 2-(3'-chlorophenyl)-3-isothiazolone, 2-phenyl-3-isothiazolone, 2-(2'-chlorophenyl)-3-isothiazolone, 2-n-pentyl-3-isothiazolone, 4,5-dichloro-2-tert-octyl-3-isothiazolone, 4-chloro-2-n-octyl-3-isothiazolone, 4-bromo-2-n-octyl-3-isothiazolone, 4-bromo-2-(4'-chlorophenyl)-3-isothiazolone, 4-bromo-2-tert-butyl-3-isothiazolone, 2-trichlorobenzyl-3-isothiazolone, 2-sec-butyl-3-isothiazolone, and 2-(4'-methylphenyl)-3-isothiazolone.
Most preferable are 5-chloro-2-hexyl-3-isothiazolone, 2-n-decyl-3-isothiazolone, 2-n-octyl-3-isothiazolone, 2-cyclohexyl-4,5-dichloro-3-isothiazolone(4,5-dichloro-2-cyclohexyl-4-isot hiazolin-3-one), 2-n-butyl-4,5-dichloro-3-isothiazolone, 2-n-octyl-4,5-dichloro-3-isothiazolone (4,5-dichloro-2-n-octyl-4-isothiazolin-3-one), 2-n-octyl-5-chloro-3-isothiazolone and related n-butyl,n-hexyl, n-heptyl and dodecyl compounds; 2-benzyl-4,5-dichloro-3-isothiazolone, 2-(2-phenethyl)-4,5-dichloro-3-isothiazolone, 2-n-dodecyl-3-isothiazolone, 5-chloro-2p-chlorobenzyl-3-isothiazolone (5-chloro-2-p-chlorobenzyl-4-isothiazolin-3-one) and combinations of two or more of said isothiazolones, such as, 5-chloro-2-octyl-3-isothiazolone and 4,5-dichloro-2-octyl-3-isothiazolone.
The preparation and properties of isothiazolones are described in U.S. Pat. Nos. 3,761,488 and 4,105,431. U.S. Pat. No. 3,849,430 discloses a process for preparing isothiazolones. U.S. Pat. Nos. 3,870,795 and 4,067,878 describe metal salt stabilized solutions of 3-isothiazolones.
The 3-isothiazolones used in this invention possess growth inhibiting effects--microbiostatic or microbiocidal or both of them--against a wide variety of microorganisms, including bacteria and fungi, the latter class including molds and yeasts.
The term "control", as employed in the specification and claims means any adverse effect on the existence or growth of any living organism or microorganism which includes a complete killing action (bactericidal action), eradication, or arresting in growth (bacteristatic action).
To further demonstrate the broad-spectrum microbiostatic activity of the 3-isothiazolones against microorganisms known to infect living mammalian hosts the minimum inhibitory concentrations (MIC) of three isothiazolones were determined against a wide variety of organisms, including bacteria and fungi. The results are reported below in Tables I, II and III. Note that these amounts are less than what is contained in the elastomers, but is representative of the minimum amount which must come to the surface of the device to be effective.
TABLE I ______________________________________ Biological Profile of 5-chloro-2-(p-chlorobenzyl)- 4-isothiazolin-3-one MIC, ppm.sup.1 ______________________________________ Bacteriostatic Activity Escherichia coli 8 Pseudomonas aeruginosa 8 Staphylococcus aureus 4 Fungistatic Activity Candida albicans (yeast) 4 Aspergillus niger 4 Aureobasidium pullulans 8 ______________________________________ .sup.1 Minimum Inhibitory Concentration, past per million
TABLE II ______________________________________ Biological Profile of 4,5-Dichloro-2-cyclohexyl- 4-isothiazolin-3-one MIC, ppm ______________________________________ Bacteriostatic Activity Escherichia coli 16 Pseudomonas aeruginosa 62 Staphylococcus aureus 10 Fungistatic Activity Candida albicans (yeast) 0.5 Aspergillus niger 0.5 Aureobasidium pullulans 0.5 ______________________________________
TABLE III ______________________________________ Biological Profile of 4,5-Dichloro-2-n-octyl- 4-isothiazolin-3-one Active Ingredient MIC, ppm ______________________________________ Test Bacterium Escherichia coli 16 Pseudomonas aeruginosa 16 Staphylococcus aureus 4 Fungistatic Activity Candida albicans (yeast) 5 Aspergillus niger 9 Aureobasidium pullulans 5 ______________________________________
Examples 1 to 4 illustrate the fundamental biological activity of the isothiazolones in both polyvinyl chloride and polysilane substrates. Comparisons with commercially available antibiotics in the same substrates are shown in Example 5. Finally, in Examples 6 and 7 actual devices incorporating an isothiazolone are tested for efficacy in resisting infection in animal models.